Herpes simplex type-2 (HSV-2) infection has been consistently identified as a risk factor for HIV acquisition, with 2-5-fold increased risk of HIV acquisition in HSV-2 seropositive persons. A proofof- concept, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of HSV-2 suppression among HSV-2+ persons at high risk of HIV was initiated in 2001 among heterosexual women in Zambia, Zimbabwe, and South Africa and men who have sex with men (MSM) in the U.S. and Peru. With RO1 and HPTN funding, the trial has enrolled 1430 persons. This application requests funds to complete the trial due to delays and new operational and regulatory requirements. The hypothesis is that standard doses of daily acyclovir 400 mg bid will reduce HIV incidence by 50% in heterosexual women and MSM by decreasing rates of clinical and subclinical HSV-2 reactivation. Specific aims are: 1) To measure the efficacy of daily generic acyclovir 400 mg bid in preventing HIV acquisition among HSV-2 seropositive, HIV-negative heterosexual women and MSM at high risk of HIV infection; 2) To determine the effect of twice daily acyclovir suppressive therapy on reducing the frequency of genital ulcers and subclinical HSV-2 reactivation among HSV-2 seropositive, HIV-negative persons; and 3) To assess adherence with twice daily acyclovir suppressive therapy among HSV-2 seropositive, HIVnegative persons. With recent data strengthening the association between HSV-2 reactivation, higher plasma HIV RNA levels, and faster HIV disease progression, a fourth aim has been added: 4) To measure the efficacy of twice daily acyclovir suppressive therapy on HIV plasma viral RNA levels during the first 6 months after HIV infection. Hypothesis: Acyclovir 400 mgbid will lower HIV RNA at setpoint, potentially resulting in slower disease progression and lower infectivity to partners. The trial will enroll 2820 (1410/arm) African women and MSM with 18 months follow-up for HIV acquisition. Implementation has been excellent (92% follow-up at 6 months), high' adherence to study drug (93.4% of visits reported 75% of study drug taken); and no serious adverse events related to study drug. Overall HIV acquisition rate has been 2.5% (95% Cl 0.9 to 4.1), indicating enrollment of high risk persons and that the trial will answer the study question. Given high HSV-2 infection rates globally in persons at risk for HIV, this approach could have great public health impact by providing a safe, acceptable and cost-effective method to reduce HIV susceptibility. [unreadable] [unreadable]